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Biomedical subjects

P Heller

Publications and source records attributed to P Heller.

At least 19 recordsLinked to original sources
PubMed1998

Endocrine and vagal controls of sympathetically dependent neurogenic inflammation.

Recently the very significant role of the postganglionic sympathetic neuron (PGSN) terminal in the production of neurogenic inflammation has been appreciated. An important model of this sympathetically dependent inflammation is venular plasma extravasation (PE) and neutrophil attraction produced by local intra-articular injection of the potent inflammatory mediator bradykinin (BK). Sympathetic-dependent PE in the synovium has been proposed as a protective mechanism in arthritis. In a recent series of studies, a novel mechanism has been discovered by which activation of primary afferent nociceptors exerts a potent feedback inhibition of PGSN-dependent PE. Activation of nociceptive afferents was shown to be involved in this feedback system. Such a negative feedback control of the acute inflammatory response would have survival value; the inflammatory response, as initiated by a high degree of positive feedback, and the inflammatory process itself when persisting can result in significant tissue injury. If indeed HPA axis activity plays a significant physiological role in the modulation of neurogenic inflammation, then physiological processes that modulate the HPA axis would be expected to influence neurogenic inflammation. A dramatic effect of this kind has been demonstrated, in the rat, for vagal afferent activity. In the presence of subdiaphragmatic (or celiac branch) vagotomy, the potency of nociceptive afferent activity to inhibit sympathetically dependent, BK-induced PE was increased by four orders of magnitude compared to vagus-intact animal. Hypoactivity or hyperactivity of these vagally mediated mechanisms could contribute to diseases characterized by either an inadequate or an exaggerated inflammatory response.

Animals↗
PubMed1998

Concomitant irradiation and dose-escalating carboplatin for locally advanced carcinoma of the uterine cervix: an updated report.

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.

Adult↗
PubMed1997

Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.

Sporadic basal cell carcinoma (BCC) is the most common type of malignant cancer in fair-skinned adults. Familial BCCs and a fraction of sporadic BCCs have lost the function of Patched (Ptc), a Sonic hedgehog (Shh) receptor that acts negatively on this signalling pathway. Overexpression of Shh can induce BCCs in mice. Here we show that ectopic expression of the zinc-finger transcription factor Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. We also show that Shh and the Gli genes are normally expressed in hair follicles, and that human sporadic BCCs consistently express Gli1 but not Shh or Gli3. Because Gli1, but not Gli3, acts as a target and mediator of Shh signalling, our results suggest that expression of Gli1 in basal cells induces BCC formation. Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli1 induction and sporadic BCC formation, as they do not occur consistently. Thus any mutations leading to the expression of Gli1 in basal cells are predicted to induce BCC formation.

Animals↗
PubMed1997

Intra- and perioperative complications associated with tandem and colpostat application for cervix cancer.

PURPOSE: The purpose of this study was to chronicle the acute morbidity associated with the implantation of tandems and colpostats in women with carcinoma of the cervix; to determine factors that predispose to the development of such complications; and to assess whether the use of ultrasound allowed the apparatus to be safely implanted in women at relatively high risk for perforation of hollow viscous organs. METHODS: A database from two Philadelphia institutions was used to assess the aforementioned factors among 143 tandems/colpostats inserted into 100 women with cervix cancer. Twenty patients had insertion under ultrasound guidance because of stenotic cervical os, fibrosis from external-beam irradiation, indeterminate orientation of endometrial cavity axis, or previous perforation. Univariate and multivariate analyses were performed to identify predictors of intra- and perioperative complications. RESULTS: Intraoperative complications occurred in 7 of 143 placements (5%). These included uterine perforations (n = 4), vaginal lacerations (n = 2), and one instance of bladder perforation. Only older age, whether entered as a continuous or a dichotomous variable, was associated statistically with these complications. Perioperative complications (e.g., fever, bowel obstruction, exacerbation of chronic obstructive pulmonary disease, cardiac complication) occurred in 54 of 143 implanted women. In univariate analysis, older age and underlying chronic obstructive pulmonary disease (COPD) appeared to be associated with perioperative complications. A multivariate analysis showed that underlying COPD predisposed to perioperative complications during the first implant and that age over 60 years independently predicted for complications during any implant. CONCLUSIONS: Intraoperative complications are relatively rare events. Ultrasonography seems to allow safe intrauterine insertion of the tandem despite the selection of difficult cases for this adjunctive imaging tool. Patient age over 60 years independently predicts for perioperative complications. COPD predicts for perioperative complications during the first but not the second implant, implying that physicians are able to optimize the medical management of pulmonary disease to allow a second implant to be performed more safely.

Adult↗
PubMed1996

Phase I/II study of concomitant irradiation and carboplatin for locally advanced carcinoma of the uterine cervix: an interim report.

The outcome of women treated with either definitive irradiation alone or in combination with cisplatin-based chemotherapy for locally advanced (>IIb) squamous cell carcinoma of the cervix has been disappointing. To improve upon our reported results with irradiation alone, a trial using irradiation plus carboplatin chemotherapy was designed for these patients. Twenty-seven women with unresectable squamous cell carcinoma of the uterine cervix were referred to our institution between July 1991 and September 1994. Seven of these patients were enrolled in a phase I/II protocol combining concurrent irradiation and carboplatin chemotherapy. Megavoltage irradiation was used to deliver 45-50.4 Gy to the pelvis (and paraaortic chain when nodes were involved) through a multiple-field technique followed by the application of Fletcher-Suit-Delclos tandem and ovoids to boost the point A dose to 85 Gy. Chemotherapy consisted of intravenous carboplatin (60 mg/m2) administered in conjunction with irradiation to a total dose of 300 mg/m2. The enrolled patients consisted of six women with stage IIIb disease and one with stage IIa with concomitant paraaortic adenopathy. All seven patients enrolled in the study completed the planned course of treatment and tolerated the treatment without severe acute morbidities. No dose modifications were required for the radiation therapy regimen. For one patient, a dose of carboplatin was withheld to allow recovery from thrombocytopenia. The overall response rate was 100% (four complete response, three partial response). The combination of concurrent irradiation (pelvic or pelvic + paraaortic fields) and carboplatin chemotherapy can be safely administered to patients with locally advanced squamous cell carcinoma of the cervix. The treatment is well tolerated and is associated with a high rate of response. Longer follow-up will be necessary to assess the durability of response. In the meantime, we have elected to escalate the dose of carboplatin (90 mg/m2) in the hope of increasing the rate of complete response without incurring unacceptable toxicity.

Adult↗
PubMed1996

Safety, efficacy and cost of three cervical cytology sampling devices in a prenatal clinic.

OBJECTIVE: To evaluate and compare the safety, efficacy and cost of three cervical cytology sampling devices in pregnant women presenting for prenatal care to the obstetrics clinic, at Medical College of Pennsylvania Hospital. STUDY DESIGN: From September 7, 1993, to November 5, 1993, 61 cervical cytologic smears were obtained using the Cell-Sweep. From November 8, 1993, to January 7, 1994, 66 smears were obtained using the Ayre spatula/Cytobrush, and from January 10, 1994, to February 18, 1994, 55 smears were obtained using the Ayre spatula/cotton swab. The rate of smears with no endocervical component or with epithelial cell abnormality was determined for each group. The patients' medical records were reviewed retrospectively to determine complications occurring within two weeks of smear collection. RESULTS: Fifteen (25%) smears in the Cell-Sweep group, one (1.5%) in the Cytobrush group and nine (16%) in the cotton swab group were satisfactory but limited by absence of an endocervical component (P < .0006). None of the smears were unsatisfactory. Eleven (18%) smears in the Cell-Sweep group, eight (12%) in the Cytobrush group and nine (16%) in the cotton swab group revealed an epithelial cell abnormality (P = .643). For all three groups there was a low rate of spontaneous abortion, preterm spontaneous rupture of membranes or preterm labor occurring within two weeks of collection. There was no statistically significant difference in these complications between the three groups (P = .7). The Ayre spatula/cotton swab is the least expensive device. CONCLUSION: The Ayre spatula/cotton swab was the most satisfactory of the three methods tested for obtaining cervical cytology during pregnancy. It is safe and cost-effective and identifies the same proportion of epithelial cell abnormalities as the Ayre spatula/Cytobrush and the Cell-Sweep.

Abortion, Spontaneous↗
PubMed1996

Clinical Significance of a cervical cytologic diagnosis of atypical squamous cells of undetermined significance. Favoring a reactive process or low grade squamous intraepithelial lesion.

OBJECTIVE: To define the clinical significance of qualifying the cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS) as favoring either a reactive process or a low grade squamous intraepithelial lesion (LSIL) in an effort to provide management guidelines. STUDY DESIGN: A total of 118 consecutive nonpregnant women with a cytological diagnosis of ASCUS favoring either a reactive process or LSIL were evaluated in our colposcopy clinic by repeat cervical cytologic smear, colposcopy and colposcopically directed biopsies and/or endocervical curettage, as indicated. RESULTS: Of the 58 patients evaluated for a smear of ASCUS, favoring a reactive process, 5 (8.6%) had cervical intraepithelial neoplasia (CIN) CIN 1 documented by biopsy. None had a high grade lesion. Twenty-six (45%) of the 58 patients who had a cytologic diagnosis of ASCUS favoring a reactive process had a repeat smear that was normal. None was found to have CIN. Of the 60 patients who had a cervical diagnosis of ASCUS favoring LSIL, 9 (15%) had CIN 1 or CIN 2. Nineteen (32%) of the 60 patients who had a cytologic diagnosis of ASCUS favoring LSIL had a repeat smear that was normal. One of these patients had CIN 1 on biopsy. The sensitivity of a repeat smear, in this limited series, after an initial smear of ASCUS favoring a reactive process is 100%, while it was 66% after an initial smear of ASCUS favoring LSIL. CONCLUSION: This study showed that in our laboratory a cytologic diagnosis of ASCUS favoring either a reactive process or LSIL is associated with a very low risk that the patient is haboring CIN. In the patient whose initial smear shows ASCUS favoring a reactive process, a repeat smear that is normal is reassuring. The patient whose smear shows ASCUS favoring LSIL probably requires further evaluation even in the presence of a normal repeat smear.

Adolescent↗
PubMed1994

The correlation between HIV seropositivity, cervical dysplasia, and HPV subtypes 6/11, 16/18, 31/33/35.

Twenty-one human immunodeficiency virus (HIV) seropositive patients were studied to determine the prevalence of cervical dysplasia, the distribution of human papilloma virus (HPV) subtypes, and the utility of cytologic diagnosis in this population. The patients ranged in age from 18 to 41 years. HIV infection was diagnosed in all patients by ELISA method and confirmed by Western blot. Patients were interviewed to document risk factors for HIV infection and cervical dysplasia. All were examined colposcopically and identifiable lesions were biopsied. In patients with normal colposcopic findings four quadrant biopsies were performed. Cervical and endocervical smears were obtained on all patients at the time of colposcopy and blood was collected for T-cell studies. Eighteen patients (86%) had abnormal cytologic findings. The Pap smear was able to identify 10 of 13 biopsy-proven epithelial abnormalities. In 14 patients there was sufficient tissue for HPV typing by in situ hybridization; the HPV subtypes identified were 6/11 (10 patients), 16/18 (9 patients), and 31/33/35 (9 patients). Dysplasia was present in 11/14 (79%) of the specimens submitted for subtyping. The absolute CD4 cell counts were 342 per mm3 for the dysplasia group and 281 per mm3 for the patients without dysplasia. Patients with dysplasia did not differ significantly from patients without dysplasia in regard to risk factors for cervical dysplasia, including history of STD, tobacco use, multiple sexual partners, age at first coitus, and parity. In addition, history of medication use and risk factors associated with HIV infection were similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Chronic actinic dermatitis. An immunohistochemical study of its T-cell antigenic profile, with comparison to cutaneous T-cell lymphoma.

Chronic actinic dermatitis (CAD) describes a persistent photosensitivity disorder in the absence of continued exposure to photosensitizers; it is characterized by a T-cell infiltrate within the epidermis and dermis. The purpose of this study was to characterize the T-cell infiltrate better immunohistochemically. Serial cryostat sections of fresh-frozen punch biopsy specimens of skin were analyzed in 11 patients with CAD and 3 patients with erythrodermic cutaneous T-cell lymphoma (CTCL). Monoclonal antibodies against the pan T-cell, pan B-cell, and T-cell subsets and the T cell-receptor (TCR) antigens were used. CD8-positive (T-suppressor-cytotoxic) cells were predominant in the epidermis of CAD, while CD4-positive (T-helper) cells were predominant in the epidermis and dermis of CTCL. CDw29-positive (T-memory) cells were predominant in all cases. The number of BF1 (beta-chain constant region of the TCR)-positive cells approximated the number of CD3-positive cells in all CAD cases but was significantly lower than the number of CD3-positive cells in two of three cases of CTCL. There was no clustering or preferential staining with any of the beta-chain variable-region antibodies in any of the specimens. These results indicate that CAD has a characteristic immunophenotype distinct from that of most cases of CTCL and that discordance between BF1 and CD3 expressions did not occur in the CAD cases.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1994

The Cell-Sweep. A new cervical cytology sampling device.

The Cell-Sweep, a new cervical cytology sampling device, was prospectively evaluated. From September 1, 1992, to October 31, 1992, 548 cervical cytology smears were prepared using the Cell-Sweep. They were compared to 524 cervical smears performed between January 1, 1993, and February 28, 1993, using the Cytobrush and Ayre spatula. One smear in the Cell-Sweep group and nine in the Cytobrush/Ayre spatula group were unsatisfactory for evaluation secondary to drying artifact (P < .01). Seven (1.2%) of the Cell-Sweep smears and 13 (2.4%) of the Cytobrush/Ayre spatula smears were inadequate due to obscuring of the epithelial cells by blood (P = .11). Of the smears obtained with the Cell-Sweep, 66 (12%) contained no endocervical component versus 42 (8%) of the smears obtained with the Cytobrush/Ayre spatula (P = .03). In the Cell-Sweep group there were 130 (23.7%) abnormal smears versus 110 (20.9%) in the Cytobrush/Ayre spatula group (P = .3). However, high grade squamous intraepithelial lesions (SILs) were identified in 10 (1.8%) smears obtained with the Cell-Sweep and in 2 (0.4%) obtained with the Cytobrush/Ayre spatula (P = .02). The Cell-Sweep produced a small proportion of unsatisfactory smears due to drying artifact or blood. Even though the proportion of smears lacking endocervical cells was statistically greater with the Cell-Sweep than with the Cytobrush/Ayre spatula, there was no difference in the rate of detection of atypical squamous cells and low grade SIL. The Cell-Sweep appears to detect an increased number of high grade SILs. This device deserves further study with histopathologic correlation.

Adolescent↗
PubMed1994

Alterations in the p53 and MDM-2 genes are infrequent in clinically localized, stage B prostate adenocarcinomas.

Alterations in the p53 gene have been described in a variety of human malignant neoplasms. We have examined 29 stage B prostate carcinomas for alterations in the p53 gene and for amplification of the MDM-2 gene. No evidence of mutations in the conserved exons 5 to 8 was found by polymerase chain reaction single-stranded conformation polymorphism analysis and no accumulation of p53 protein was found by immunohistochemistry. However, loss of heterozygosity at the p53 locus was observed in 11% of information cases. Amplification of the MDM-2 gene was not observed by Southern blot hybridization. In contrast, stage C and D prostate carcinomas showed accumulation of p53 protein in 33 to 66% of cases. We conclude that alterations in p53 function are infrequent in clinically localized prostate cancers but are more common in advanced cancers.

Adenocarcinoma↗
PubMed1993

Sodium dependence of the Na(+)-H+ exchanger in the pre-steady state. Implications for the exchange mechanism.

The pre-steady state time course of amiloride-sensitive Na+o uptake by the Na(+)-H+ exchanger in renal brush border membrane vesicles (BBMV) exhibits a burst phase at 0 degrees C which corresponds to the initial turnover of the exchanger (Otsu, K., Kinsella, J. L., Sacktor, B. S., and Froehlich, J. P. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 4818-4822). Investigation of the Na+o dependence of the Na(+)-H+ exchanger between 1 and 10 mM Na+ revealed that activation of the burst phase involves at least two Na+ transport sites interacting with positive cooperativity. In this study, characterization of the Na+ transport sites contributing to the burst phase was extended to include Na+ concentrations below 1 mM. Between 0.1 and 1 mM Na+ the amplitude of the burst phase in acid-loaded BBMV (pHi 5.7; pHo 7.7) exhibited a sigmoidal dependence on [Na+]o, consistent with the presence of a second class of high affinity Na+ transport sites with cooperative binding characteristics. In contrast, steady state Na+ uptake obeyed Michaelis-Menten kinetics, similar to the behavior observed previously at higher (1-10 mM) Na+o concentrations. Treatment of the vesicles with carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, which induced the formation of an inside-negative membrane potential, increased the burst amplitude but had no effect on the steady state uptake velocity. Experiments performed with alkaline-loaded BBMV (pHi 7.7; pHo 7.7), which permit only a single turnover of the exchanger, gave a simple hyperbolic dependence of the burst amplitude on [Na+]o (0.5-5 mM). We propose that the change in multiplicity of Na+ transport sites and membrane potential sensitivity that occurs in the transition between the pre-steady state and the steady state of Na+ uptake in acid-loaded vesicles reflects the presence of an oligomer which operates according to a "flip-flop" mechanism. The minimum subunit composition inferred from the biphasic [Na+]o dependence of the burst amplitude is a dimer at low (< 1 mM) Na+o levels and a tetramer at high [Na+]o. Communication between the subunits producing the complex [Na+]o dependence is controlled by the intravesicular (cytoplasmic) H+ modifier site. Under alkaline conditions (pH 7.7), where this site is unoccupied, the subunits behave as independent units and cease operation after the first turnover. Occupation of the H+ modifier site activates a conformational interaction between the subunits that leads to cooperative Na+o binding, alternation of the transport sites, and repetitive cycling of the Na(+)-H+ exchanger.

Amiloride↗
PubMed1993

Fetal hemoglobin reactivation in baboon and man: a short perspective.

Present concepts of the mechanism of reactivation of synthesis of fetal hemoglobin (HbF) in the adult under conditions of erythropoietic stress are briefly reviewed. Since HbF can be considered an effective natural antisickling agent, the reactivation of its synthesis in patients with sickle cell anemia as a desirable therapeutic goal has been extensively explored since the discovery in 1982 that 5-azacytidine increases HbF levels in the baboon. Hydroxyurea (HU) has become the most widely used agent, although its effectiveness in increasing HbF levels and the number of F cells is highly variable. Recent investigations are cited showing that other agents such as butyrate, and the addition of recombinant hemopoietic growth factors, such as erythropoietin and stem cell factor, especially in combination with HU, offer important therapeutic possibilities. Transacting nuclear proteins are briefly discussed as possibly having a future role in the efforts of stimulating gamma-chain synthesis.

Anemia, Sickle Cell↗
PubMed1993

Modulation of bradykinin-induced plasma extravasation in the rat knee joint by sympathetic co-transmitters.

We describe the contribution of various sympathetic post-ganglionic neuron mediators to bradykinin-induced plasma extravasation in the knee joint of the rat. Co-perfusion of the sympathetic post-ganglionic neuron mediators, norepinephrine or neuropeptide Y with bradykinin resulted in diminished plasma extravasation. In contrast, the putative sympathetic post-ganglionic neuron mediators of bradykinin-induced plasma extravasation, namely prostaglandin E2, ATP, the selective adenosine A2-receptor agonist, CGS21680 or the endothelium-derived relaxing factor (as its precursor L-arginine) all greatly enhanced bradykinin-induced plasma extravasation, but produced little or no increase in plasma extravasation administered alone. The data show that sympathetic post-ganglionic neuron-derived mediators may either inhibit or enhance plasma extravasation induced by bradykinin, and we hypothesize that differential release of mediators from the sympathetic post-ganglionic neuron terminal, in response to varying stimuli, regulates local plasma extravasation during inflammation.

Adenosine↗
PubMed1991

A homeodomain protein binds to gamma-globin gene regulatory sequences.

Developmental regulation of gamma-globin gene expression probably occurs through developmental-stage-specific trans-acting factors able to promote the interaction of enhancer elements located in the far upstream locus control region with regulatory elements in the gamma gene promoters and 3' A gamma enhancer located in close proximity to the genes. We have detected a nuclear protein in K562 and baboon fetal bone marrow nuclear extracts capable of binding to A+T-rich sequences in the locus control region, gamma gene promoter, and 3' A gamma enhancer. SDS/polyacrylamide gel analysis of the purified K562 binding activity revealed a single protein of 87 kDa. A K562 cDNA clone was isolated encoding a beta-galactosidase fusion protein with a DNA binding specificity identical to that of the K562/fetal bone marrow nuclear protein. The cDNA clone encodes a homeodomain homologous to the Drosophila antennapedia protein.

Animals↗